Abstract Metal orthopedic implants are common devices used for restoring musculoskeletal joint function and patient mobility. Given the large number of orthopedic joint reconstructions conducted each year, it is important to minimize rates of aseptic implant loosening which causes pain and often leads to revision surgery. Therapeutics that modify endogenous epigenetic processes are promising for the treatment of many musculoskeletal disorders, including osteopenia and osteoporosis, yet the delivery mode and molecular mechanisms that act to diminish clinical symptoms are in need of further investigation. The central hypothesis of the proposed project is that osseointegration of orthopedic implants can be improved by modulating the biological properties of endogenous skeletal repair cells using epigenetic inhibitors. Based on recent preliminary data, this amended proposal has evolved to address the specific working model that epigenetic drugs can be used to stimulate paracrine signaling (e.g., BMP2 activity) to drive endogenous skeletal repair cells into the osteoblast lineage. New data I generated show that human mesenchymal stromal cells (both adipose and bone tissue-derived) attach to porous metal orthopedic implants, as well as proliferate and deposit an extracellular matrix. Additional preliminary data reveal that Ezh2 inhibition can bolster the differentiation of MC3T3 pre-osteoblasts, both in vitro and in vivo. Based on these preliminary data, this study will (i) determine the in vivo effects of Ezh2 delivery before, during or after reconstructive orthopedic surgery (Aim 1), and (ii) examine the mechanism of Ezh2 inhibition by measuring the effects of blocking paracrine signaling (e.g., BMP2) on osteoblast differentiation in vitro (Aim 2). My long term goals are to develop strategies for localized delivery of bone anabolic therapeutic reagents to address the increasing demands of an expanding, aging, and increasingly active human population. These studies should ultimately lead to the development of surgeon- assembled adjuvants and become part of routine orthopedic practices, as well as support my career progression as an independent investigator capable of executing clinically relevant translational research similar to that proposed here.